Reciprocal Regulation of Myocardial microRNAs and Messenger RNA in Human Cardiomyopathy and Reversal of the microRNA Signature by Biomechanical Support

Abstract

Background-Much has been learned about transcriptional control of cardiac gene expression in clinical and experimental congestive heart failure (CHF), but less is known about dynamic regulation of microRNAs (miRs) in CHF and during CHF treatment. We performed comprehensive microarray profiling of miRs and messenger RNAs (mRNAs) in myocardial specimens from human CHF with (nϭ10) or without (nϭ17) biomechanical support from left ventricular assist devices in comparison to nonfailing hearts (nϭ11). Methods and Results-Twenty-eight miRs were upregulated Ͼ2.0-fold (PϽ0.001) in CHF, with nearly complete normalization of the heart failure miR signature by left ventricular assist device treatment. In contrast, of 444 mRNAs that were altered by Ͼ1.3-fold in failing hearts, only 29 mRNAs normalized by as much as 25% in post-left ventricular assist device hearts. Unsupervised hierarchical clustering of upregulated miRs and mRNAs with nearest centroid analysis and leave-1-out cross-validation revealed that combining the miR and mRNA signatures increased the ability of RNA profiling to serve as a clinical biomarker of diagnostic group and functional class. Conclusions-These results show that miRs are more sensitive than mRNAs to the acute functional status of end-stage heart failure, consistent with important functions for regulated miRs in the myocardial response to stress. Combined miR and mRNA profiling may have superior potential as a diagnostic and prognostic test in end-stage cardiomyopathy.

Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers

“…The down-regulation of the myomir mir-1-1(4) therefore supports a myogenic dedifferentiation in human HF. The reported regulation in human HF and fetal myocardium, however, has been controversial, including observations of increased mir-1-1(4) expression (11,14). Furthermore, we only detected marginal differences in miRNA expression between ICM and DCM hearts and no differences before and after LVAD support, both of which are supported by another recent RNAseq study (17), but contrasted with a microarray-based study reporting more dramatic differences in their comparison of hearts before and after LVAD treatment (14).…”

“…The reported regulation in human HF and fetal myocardium, however, has been controversial, including observations of increased mir-1-1(4) expression (11,14). Furthermore, we only detected marginal differences in miRNA expression between ICM and DCM hearts and no differences before and after LVAD support, both of which are supported by another recent RNAseq study (17), but contrasted with a microarray-based study reporting more dramatic differences in their comparison of hearts before and after LVAD treatment (14). It is conceivable that distinctive myocardial miRNA changes reflecting heterogeneous genetic or environmental etiologies as well as the myocardial response to pharmacologic and nonpharmacologic therapies exist and that these changes are detectable at early stages of HF.…”

“…S1) were shown to contribute to muscle or myocardial function (8, 9). miRNAs and other classes of RNA have been profiled in failing human myocardium (10)(11)(12)(13)(14)(15)(16)(17), and a selected subset was also investigated as circulating biomarkers in HF (18)(19)(20)(21)(22)(23)(24). However, in these studies heart tissue and circulating miRNA abundance changes were not acquired simultaneously to correlate changes in tissue versus circulating miRNA composition.…”

Exercício físico e microRNAs: novas fronteiras na insuficiência cardíaca

“…While some authors 22,27,28 observed a reduction in miR-1 in ischemic and non-ischemic dilated cardiomyopathy, others observed an increase 21,29 . Han et al 25 suggest the possibility that miR-1 is reduced in hypertrophy, but returns to normal or above normal when the condition progresses to HF.…”

Expression of miR-208b and miR-499 in Greek Patients with Acute Myocardial Infarction

“…It regulates the expression of the beta myosin heavy chain, resulting in the enhancement of myocardial oxygen metabolism and tolerance (24). It has also been demonstrated that the expression levels of miR-499 exhibit a significant change in certain heart diseases, including AMI (25,26).…”